How the innate immune system discriminates pathogen attack from colonization with harmless commensal microbes is a fundamental unresolved question. One model suggests that the host responds to endogenous ligands generated as a consequence of the tissue damage associated with infection (DAMPs) and that these ligands must be encountered alongside the better-characterized Microbial-Associated Molecular Patterns to induce a robust inflammatory response. Another possibility is suggested by our recent discovery that host proteins that have undergone very specific post-translational modifications due to the activity of microbial-derived effectors or toxins may themselves trigger an innate immune response. These Virulence-Associated Molecular Patterns (VAMPs) can be considered as a subset of DAMPs that are found specifically after exposure to virulent pathogens that deliberately modify host proteins. Importantly, the response to these modified-self proteins occurs early in the course of infection and can induce strong and potentially protective immune responses. We refer to these as effector-triggered immune (ETI) responses. Here we propose studies to identify and better understand how the host senses and responds to bacterial effectors and the role that effector-triggered immunity plays in initiating and fine-tuning our response to virulent pathogens.